JP3418688B2 - Novel urethanes derived from azacycloalkanes, their thio and dithio analogs, their salts, pharmaceutical compositions containing these compounds, their use and their preparation - Google Patents

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to novel urethanes derived from azacycloalkanes, their thio and dithio analogs, their salts with physiologically acceptable organic and inorganic acids, the preparation of these compounds. The present invention relates to methods and pharmaceutical compositions containing them.
The compounds of the present invention are inhibitors of cholesterol biosynthesis, especially the enzyme 2, which is a major enzyme of cholesterol biosynthesis,
It is an inhibitor of 3-epoxysqualene-lanosterol-cyclase. The compounds of the invention are suitable for the treatment and prevention of hyperlipidemia, hypercholesterolemia and atherosclerosis. Other possible applications are in the treatment of hyperproliferative skin and vascular diseases, tumors, gallstone problems and mycoses.

BACKGROUND OF THE INVENTION Compounds affecting cholesterol biosynthesis are important in the treatment of several diseases. These include, among others, hypercholesterolemia and hyperlipidemia, which are risk factors for the development of atherosclerotic vascular changes, and their sequelae, such as coronary heart disease, cerebral ischemia, intermittent glaucoma and gangrene. Is mentioned. The importance of elevated serum cholesterol levels as a major risk factor for the development of atherosclerotic vascular changes is generally known. Extensive clinical research
We have found that the risk of developing coronary heart disease can be reduced by lowering serum cholesterol (Current Opinion in Lipidology 2 (4), 234 [199
1); Exp. Opin. Ther. Patents 7 (5), 441-455 〔199
7)). Most of the cholesterol is synthesized in the body itself and a small fraction is taken with food,
Inhibition of biosynthesis is a particularly attractive way to reduce elevated cholesterol levels.

In addition, other possible applications of cholesterol biosynthesis inhibitors are their use in the treatment of hyperproliferative skin and vascular diseases and tumors, the treatment and prevention of gallstone problems and the treatment of fungal diseases. The latter case involves the intervention of ergosterol biosynthesis in fungal organisms, which proceeds substantially like cholesterol biosynthesis in mammalian cells. Cholesterol or ergosterol biosynthesis occurs starting from acetic acid via a number of reaction steps. This multi-step process offers several possible interventions, the following of which are examples: To suppress the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) -synthase, β-lactone and β-lactam, which have potential antihypercholesterolemic activity, are mentioned (J.
Antibiotics 40, 1356 (1987), U.S. Pat.No. 4,751,237
, EP-A-0 462 667, U.S. Pat. No. 4,983,597). Examples of inhibitors of the enzyme HMG-CoA-reductase are mevinolin type 3,5-dihydroxycarboxylic acids and their β-lactones, of which lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin are hypercholesterolemic. Used for treatment. Other possible applications for these compounds are fungal infections (US Pat. No. 4,375,475, E
PA-0 113 881, US Patent No. 5,106,992), skin disorders (E
PA-0 369 263) and gallstone problems and tumor diseases (US Pat. No. 5,106,992, Lancet 339, 1154-1156 [1992]).

Inhibition of smooth muscle cell proliferation by lovastatin is due to Cardiovasc. Drugs. Ther. 5, Suppl. 3, 354 [199
1]. Tocotrienol, an unsaturated analogue of vitamin E, and its analogues constitute another class of substances that act on HMG-CoA-reductase (Exp. Op.
in. Ther. Patents 7 (5), 446 [1997]). Inhibitors of the enzyme squalene-synthase are, for example, isoprenoid- (phosphinylmethyl) -phosphonates, whose suitability for treating hypercholesterolemia, gallstone problems and tumor diseases EP-A-0 409 181 and J. Med. . Chemistry 3
4, 1912 [1991]), and also α-
Phosphonosulfinate compound (EP-A-0 698 609), compounds J-104, 118 and J-104, 123 (Tetrahedron 52, 13881-1
3894, [1996]) and cyclobutane derivatives (WO 96/3315
9). Exploration of squalene-synthase inhibitors has been reported in Exp. Opin. Ther. Patents 7 (5), 446-448 [199].
7].

Known inhibitors of the enzyme squalene-epoxidase are allylamines, such as naphthidine and terbinafine, which have been used in the treatment of combating fungal diseases, and also allylamine NB-598, which has antihypercholesterolemic activity. J. Biol. Chemistry 265,
18075-18078 [1990]) and fluorosqualene derivatives having hypocholesterolemic activity (US Pat. No. 5,011,859)
No.). Furthermore, piperidine and azadecalin, which have potential hypocholesterolemic and / or antifungal activity, have been described, the mechanism of their activity is not well described, and they are squalene epoxidase inhibitors and / or 2 , 3-epoxysqualene-lanosterol-cyclase inhibitor (EP-A-0 4
20 116, EP-A-0 468 434, U.S. Pat.No. 5,084,461 and E
PA-0 468 457). Other examples are Exp. Opin. Ther. Paten
ts 7 (5), 448-449 [1997]. Enzyme 2,3
-Examples of inhibitors of -epoxysqualene-lanosterol-cyclase are diphenyl derivatives (EP-A-0 464 465),
Aminoalkoxybenzene derivative (EP-A-0 410 359, J.
Lipid. Res. 38, 373-390, [1997]) and a piperidine derivative (J. Org. Chem. 57, 2794-2903 [1992] (these have antifungal activity). Decalin, azadecalin and indane derivatives (W
O 89/08450; J. Biol. Chemistry 254, 11258-11263
(1981); Biochem. Pharmacology 37, 1955-1964 (19
88] and J 64 003 144), and also 2-aza-2,3-dihydro-squalene and 2,3-epiminosqualene (Biochem.
harmacology 34, 2765-2777 (1985)), squalenoid-epoxide-vinyl ether (J. Chem. Soc. Perki
n Trans. I, 461 (1988)) and 29-methylidene-2,3-oxidosqualene (J. Amer. Chem. Soc. 113, 9673-967).
4 [1991]). Other examples include pyridine derivatives and pyrimidine derivatives (WO 97/06802), heterobicyclic alkylamines (WO 96/11201), imidazole derivatives (EP-A-0 757 988) and isoquinoline derivatives (J. Med. C).
hemistry 39, 2302-2312, [1996]). Other compounds mentioned are urea (DE-A-4 438 021), oxime (D
EA-4 412 692), some amides (DE-A-4 407 134, DE-
A-4 407 135, DE-A-4 407 136, DE-A-4 407 138, DE-A-
4 407 139, DE-A-4 412 691, DE-A-4 437 999, DE-A-4
438 000, DE-A-4 438 020, DE-A-4 438 082, DE-A-4 43
8 029, DE-A-4 438 054, DE-A-4 438 055, DE-A-4 438
082, DE-A-4 438 083, EP-A-0 599 203, EP-A-0 596 32
6) and esters (WO 95/29148). Another example is Ex
p. Opin. Ther. Patents 7 (5), 448-449 [1997].

Finally, inhibitors of the enzyme lanosterol-14α-demethylase also include steroid derivatives with potential antihyperlipidemic activity, which at the same time affect the enzyme HMG-CoA-reductase (US Pat. 5,041,431; J. Biol. Chemistry 266, 20070-20078.
[1991]; U.S. Pat. No. 5,034,548). This enzyme also
It is suppressed by azole type antifungal agents that constitute N-substituted imidazoles and triazoles. As this class,
Examples include the commercially available antifungal agents ketoconazole and fluconazole. The compounds of general formula I below are new. Surprisingly, they are the enzyme 2,3-epoxysqualene.
-Lanosterol-cyclase (International classification: EC 5.4.99.
It was found to be a highly effective inhibitor of 7). The enzyme 2,3-epoxysqualene-lanosterol-cyclase is a major step in cholesterol or ergosterol biosynthesis, namely 2, to lanosterol, the first compound with a steroid structure in the biosynthetic cascade,
Catalyzes the conversion of 3-epoxysqualene. Inhibitors of this enzyme are expected to benefit from high selectivity over inhibitors of early stages of biosynthesis, such as HMG-CoA-synthase and HMG-CoA-reductase. Inhibition of these early stages of biosynthesis results in a decrease in mevalonate produced by biosynthesis, and thus the mevalonate-dependent substances dolichol, ubiquinone and isopentenyl-tR.
It may have a negative effect on the biosynthesis of NA (J. Biol.
Chemistry 265, 18075-18078 [1990]). If the step of biosynthesis after the conversion of 2,3-epoxysqualene to lanosterol is suppressed, there is a risk of accumulation of in vivo intermediate products with steroidal structures and induction of the toxic effects produced thereby. This has been described, for example, in the case of the desmosterol-reductase inhibitor triparanol. This substance needed to be withdrawn from the market due to the formation of cataracts, ichthyosis and hair loss (J. Biol. Chemistry 265, 18075-
18078 [1990]). As mentioned above, 2,
Inhibitors of 3-epoxysqualene-lanosterol-cyclase have been previously described in the literature. However, urethanes or their thio- or dithio-analogs are completely unknown as inhibitors of 2,3-epoxysqualene-lanosterol-cyclase.

DISCLOSURE OF THE INVENTION The present invention is suitable for the treatment and prevention of atherosclerosis and is distinguished from known active substances by their excellent antihypercholesterolemic activity together with great selectivity and thus great safety. It relates to the preparation of hypercholesterolemic substances. The compounds of the present invention also include the enzyme 2,3-epoxysqualene.
-Because of their great potency as inhibitors of lanosterol-cyclase, they can also suppress ergosterol biosynthesis in fungal organisms, so they are also suitable for treating fungal diseases. The present invention has the general formula

[0008]

[Chemical 5]

Novel urethanes derived from the azacycloalkanes and their thio and dithio analogues,
It relates to their enantiomers, diastereomers, mixtures and their salts, in particular their physiologically acceptable acid addition salts. In the formula, m represents the number 0 or 1, n represents the number 1 or 2, A is a single bond, a linear or branched C _1-8 -alkylene group, C
_{Represents a 2-8} -alkenylene group or a C _2-8 -alkynylene group (the unsaturated group is not directly bonded to the group Y), X represents an oxygen atom or a sulfur atom, and Y represents an oxygen atom or a sulfur atom. , R ¹ represents a linear or branched C _1-6 -alkyl group, C _1-4 -alkenyl group or C _1-4 -alkynyl group, the multiple bond of which is separated from the nitrogen-carbon bond, R ² Is a straight-chain or branched C
_{Represents a 1-6} -alkyl group, a C _1-4 -alkenyl group or a C _1-4 -alkynyl group, the multiple bond is separated from the nitrogen-carbon bond, or R ¹ and R ² are together with the nitrogen atom. 5 members to 7
Membered saturated heterocycle, the methylene group separated from the nitrogen atom is an oxygen atom, a sulfur atom, a -NH- group or
Optionally substituted by a -N (alkyl)-group, R ^{3 to} R ⁶
(These may be the same or different) represent a hydrogen atom or an alkyl group, R ⁷ is a C _3-7 -cycloalkyl group, optionally 1 or 2 halogen atoms or an alkyl group. A group, an alkoxy group, a phenyl group which may be substituted with a trifluoromethyl group or a cyano group or a naphthyl group, or when A does not represent a single bond, R ⁷ also represents a hydrogen atom, E Represents an oxygen atom or a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ represents a hydrogen atom, or E represents a group.
-C (R ⁹ R ¹⁰ )-(in the formula, R ⁹ represents a hydrogen atom, and R ¹⁰ together with the adjacent group R ⁸ represents a carbon-carbon bond),
Unless otherwise specified, the alkyl group contained in the above group may contain 1 to 3 carbon atoms, and the halogen atom may be a fluorine atom, a chlorine atom or a bromine atom.

Preferred compounds are those in which m represents the number 1, n represents the number 1, A represents a single bond, a linear or branched C _1-4 -alkylene group or a C _2-4 -alkenylene group, and an unsaturated group. Is not directly bonded to the group Y, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, R ¹ is a linear or branched C _1-6 -alkyl group, an allyl group or propargyl. Represents a group, the multiple bond of which is separated from the nitrogen-carbon bond, R ² represents a linear or branched C _1-6 -alkyl group, an allyl group or a propargyl group, the multiple bond of which is separated from the nitrogen-carbon bond. R ¹ and R ² together with a nitrogen atom represent a 5-membered to 7-membered saturated heterocycle, and the methylene group separated from the nitrogen atom may be substituted with an oxygen atom or a sulfur atom. well, R ³ ~R ⁶ (may be these are the same, even if also different ) Represents a hydrogen atom or a methyl group, R ⁷ is C _3-6 - cycloalkyl group, one or two halogen atoms or an alkyl group as necessary, alkoxy group, substituted by a trifluoromethyl group or a cyano group Optionally represents a phenyl group or a naphthyl group,
E represents a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ represents a hydrogen atom, or E represents a group -C.
(R ⁹ R ¹⁰ )-(in the formula, R ⁹ represents a hydrogen atom, and R ¹⁰ represents a carbon-carbon bond together with the adjacent group R ⁸ ) and unless otherwise specified, the above group The alkyl groups contained therein may each contain 1 to 3 carbon atoms, and said halogen atom may be a fluorine atom, a chlorine atom or a bromine atom, compounds of general formula I, enantiomers thereof, Diastereomers, mixtures and salts thereof, especially their physiologically acceptable acid addition salts.

M represents the number 1, n represents the number 1, A represents a single bond or a linear or branched C _1-3 -alkylene group, X represents an oxygen atom or a sulfur atom, and Y represents an oxygen atom. Or a sulfur atom, R ¹ represents a linear or branched C _1-3 -alkyl group, R 1
² represents a linear or branched C _1-3 -alkyl group, or R ¹ and R ²
Represents a piperidino group or a morpholino group together with a nitrogen atom, R ^{3 to} R ⁶ represent a hydrogen atom, and R ⁷ is a cyclohexyl group or optionally a halogen atom or an alkyl group, an alkoxy group or a trifluoromethyl group. An optionally substituted phenyl group, E represents a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸
Represents a hydrogen atom, or E represents a group -C (R ⁹ R ¹⁰ )-(wherein R ⁹ represents a hydrogen atom, and R ¹⁰ together with the adjacent group R ⁸ represents a carbon-carbon bond. Of the formula I, their enantiomers, diastereomers, mixtures and their salts, in particular their physiologically acceptable acid addition salts, are particularly preferred.

M represents the number 1, n represents the number 1, A represents a single bond or a methylene group, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, R ¹ and R ² each represents a methyl group, R ^{3 to} R ⁶ represent a hydrogen atom, R ⁷ represents a phenyl group optionally substituted by a fluorine atom or a chlorine atom or a methyl group, E is a sulfur atom, Represents a methylene group or a carbonyl group, and R ⁸ represents a hydrogen atom, or E represents a group —C (R ⁹ R ¹⁰ ) — (in the formula, R ⁹ represents a hydrogen atom, and R ¹⁰ represents an adjacent group R ⁸ Of the formula I, their mixtures and salts, especially their physiologically tolerated acid addition salts, are particularly most preferred, especially the compound (1) N- (Benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (2) N- ( Benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine, (3) N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (4) N- (4- Chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (5) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine,

(6) N- (benzylthio) thiocarbonyl-4-
[4- (dimethylaminomethyl) benzylidene] piperidine, (7) N- (4-chlorophenoxy) thiocarbonyl-4- [4- (dimethylaminomethyl) -benzyl] piperidine, (8) N- (4-chloro Phenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (9) N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (10) 4- [4- ( Dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) -carbonylpiperidine, (11) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) -thiocarbonylpiperidine and (12 ) 4- [4- (Dimethylaminomethyl) benzyl] -N- (4-fluorophenoxy) -carbonylpiperidine, mixtures and salts thereof, especially physiologically acceptable acid addition salts thereof, for example, hydrochloride, methanesulfone Most preferred is acid salt or tartrate Good Compounds of general formula I are, for example:
It can be prepared by the following method. a) general formula

[0014]

[Chemical 6]

## STR1 ## wherein m, n, E (excluding sulfinyl group), R ^{1 to} R ⁶ and R ⁸ are as defined above

[0016]

[Chemical 7]

Wherein A, X, Y and R ⁷ are as defined above and Z represents a leaving group such as a halogen atom, eg chlorine atom, bromine atom or iodine atom. Method of reacting with the compound of. The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the component is -50 in the presence of at least one equivalent of an auxiliary base.
The reaction is carried out at a temperature of from ℃ to +120 ℃, preferably from -10 ℃ to +30 ℃, optionally in the presence of a solvent. Preferred auxiliary bases are alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, alkali metal hydroxides. Acetates such as sodium or potassium acetate, and tertiary amines such as pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,
1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] undec-7-ene, as a preferred solvent, for example, diethyl ether, methylene chloride,
Examples include dichloromethane, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or a mixture thereof. If alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as auxiliary bases, water may also be added to the reaction mixture as auxiliary solvent. b) a compound of the general formula (I), wherein X and Y each represent a sulfur atom, and m, n, A, E and R ^{1 to} R ⁸ are as defined above, provided that A R represents a single bond, R ⁷
To prepare an optionally substituted phenyl group or naphthyl group) in order to prepare a compound of the general formula (II) (wherein m, n, E (sulfinyl group , R ^{1 to} R ⁶ and R ⁸ are as defined above), followed by reaction with carbon disulfide

[0018]

[Chemical 8]

(In the formula, A and R ⁷ are as defined above, provided that when A represents a single bond, R ⁷ is an optionally substituted phenyl group or naphthyl group. Not represented, and Z ¹ is a leaving group, for example, a halogen atom, for example, a chlorine atom, a bromine atom or an iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms in the alkyl moiety, Optionally represents a phenylsulfonyloxy group or a naphthylsulfonyloxy group which may be mono-substituted, di-substituted or tri-substituted with a chlorine atom or a bromine atom, a methyl group or a nitro group, and these substituents may be the same. , May be different)
The method of reacting with the alkylating agent of. The reaction is first carried out by reacting the compound of general formula (II) with lithium in a suitable solvent, for example tetrahydrofuran, dioxane, hexane or toluene, for example using n-butyllithium at a temperature of -20 ° C to -10 ° C. This is conveniently done by converting to the salt and then reacting it with carbon disulfide. The compound of general formula (IV) is then added in a suitable solvent such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide or a mixture of these solvents and the reaction is carried out at 20-60 ° C.

C) In order to prepare a compound of general formula (I) (wherein E represents a sulfinyl group), a compound of general formula (I) (wherein m, n, A, X, Y, And R ^{1 to} R ⁸ are as defined above, and E represents a sulfur atom) (preferably with sodium metaperiodate). Its oxidation is -15 ℃ to 25 ℃ in aqueous methanol or ethanol.
It is conveniently carried out using one equivalent of an oxidizing agent at ° C, eg sodium metaperiodate.

The compounds of general formula I prepared by the above methods can be purified and isolated by methods known per se, for example by crystallization, distillation or chromatography.
Furthermore, the compounds of general formula I obtained may, if desired, be resolved into their enantiomers and / or diastereomers. Thus, for example, the compounds of general formula I obtained, which occur as racemates, are obtained in a manner known per se (Allinge
r NL and Eliel EL "Topics in Stereochemist
ry ", Vol. 6, Wiley Interscience, 1971).
Compounds of general formula I which may be separated into their optical enantiomers by means of and which have at least two asymmetric carbon atoms can be prepared by methods known per se, for example by chromatography and / or fractionation. Crystallization may be resolved into their diastereomers on the basis of their physical-chemical differences, and when these compounds are obtained in racemic form, they are subsequently enantiomerized as described above. It may be divided. Enantiomers are obtained by column separation with chiral phases or recrystallization with optically active solvents, or with optically active substances, which form racemates and salts or derivatives, such as esters or amides, especially acids and their activated derivatives or alcohols. The free enantiomers are preferably separated by reacting with a diastereomeric mixture of salts or derivatives thus obtained, for example by separation based on their solubility differences. Upon action, it may be released from pure diastereomeric salts or derivatives. Commonly used optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. . The optically active alcohol may be, for example, (+)-menthol or (−)-menthol, and the optically active acyl group in the amide is, for example, (+)-or (−)-menthyloxycarbonyl. May be. Furthermore, the compounds of general formula I may be converted into their salts, especially for pharmaceutical use into their physiologically acceptable salts with inorganic or organic acids. Acids which can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The starting compounds of general formula II, where E represents a carbonyl group, can be prepared by the method described in DE 44 07 136 A1 (pp. 4-5). A starting compound of the general formula II, in which E is a methylene group or the group -C (R ⁹ R ¹⁰ )-(wherein R ⁹ represents a hydrogen atom and R ¹⁰ together with the adjacent group R ⁸ Carbon-
Represents a carbon bond) represents) DE 44 07 138 A1 (5/1144)
It can be prepared by the method described in (pp. 7-8). The compound of the general formula II (wherein E represents an oxygen atom or a sulfur atom) can be prepared by the following reaction plan.

[0023]

[Chemical 9]

A compound of formula V (wherein R ^{1 to} R ⁵ are as defined above and E is an oxygen atom or a sulfur atom) and a compound of formula VI (wherein m, n, R ⁶ and R ⁸ are as defined above, R ¹¹ represents a protecting group, for example tert.butyloxycarbonyl group, and R ¹² represents an alkyl group) reaction of the corresponding compound of formula VII Which is converted to a compound of formula II by cleavage of the protecting group R ¹¹ .
A compound of the general formula II (wherein E represents a methylene group, an oxygen atom or a sulfur atom, R ^{3 to} R ⁵ and R ⁸ represent a hydrogen atom, R ⁶
Represents a hydrogen atom or an alkyl group, and the phenyl group thereof is 1,4-disubstituted) can be prepared by the two methods shown in the reaction plans below.

[0025]

[Chemical 10]

On the other hand, the compound of formula VIII (wherein R ¹¹ represents a protecting group, preferably a 2,2,2-trichloroethoxycarbonyl group) is converted to the compound of formula IX by chloromethylation. Aminolysis of amines of formula R ¹ R ² NH with formula X
To give a compound of formula II which is converted to a compound of formula II by cleavage of the protecting group. On the other hand, a compound of formula VIII (wherein R
¹¹ represents a protecting group, preferably a trifluoroacetyl group) can be converted to the compound of formula XI by Friedel-Crafts reaction with oxalyl chloride in the presence of aluminum chloride. Aminolysis of the formula R ¹ R ² NH with amines gives the formula XII
To give a compound of formula II which is reduced by lithium aluminum hydride and cleavage of the protecting group. The compound of formula II (wherein E represents an oxygen atom or a sulfur atom, R ^{3 to} R ⁵ and R ⁸ represent a hydrogen atom, and R ⁶ represents a hydrogen atom or an alkyl group) is also prepared by the following method. You can

[0027]

[Chemical 11]

The compound of formula XIII (wherein R ¹¹ represents a protecting group, preferably a trityl group) is first converted to its lithium compound, and then the compound of formula XIV (wherein Hal is chlorine atom, bromine atom). Or represents an iodine atom) to form a compound of formula XV. Cleavage of the protecting groups gives compounds of formula II. The compounds of general formula I have valuable biological properties. They are inhibitors of cholesterol biosynthesis, especially the enzyme 2,3-epoxysqualene-lanosterol-
It is an inhibitor of cyclase. In view of their biological properties, they are used for the treatment of diseases involving cholesterol biosynthesis, in particular hypercholesterolemia, hyperlipoproteinemia and hypertriglyceridemia and their sequelae, for example coronary heart disease, Cerebral ischemia and intermittentness are suitable for the treatment and prevention of atherosclerotic vascular changes caused by row, gangrene and the like. For the treatment of these diseases, the general formula I
Compounds may be used alone for a single treatment,
It may also be used in combination with other cholesterol- or lipid-lowering substances, in which case these compounds are preferably administered as an oral preparation and, if necessary, as a rectal preparation in the form of a suppository. Possible combination partners are: -bile acid-binding resins, such as cholestyramine, colestipol, etc.-compounds that inhibit cholesterol absorption, such as sitosterol and neomycin, -2,3-epoxysqualene-lanosterol-cyclase. Compounds that inhibit cholesterol biosynthesis by mechanisms other than suppression, such as lovastatin, simvastatin, pravastatin,
HMG-CoA reductase inhibitors such as fluvastatin, atorvastatin, cerivastatin, -squalene-epoxidase inhibitors, e.g. NB 598 and similar compounds and -squalene-synthase inhibitors, e.g. isoprenoid- (phosphinylmethyl)
Compounds from the phosphonate class and squalestatin.

Other possible combination partners still mentioned are fibrates, eg clofibrate, bezafibrate, gemfibrozil, etc., nicotinic acid, its derivatives and analogues, eg acipimox and probucol. Furthermore, the compounds of general formula I are suitable for the treatment of diseases associated with excessive cell proliferation. Cholesterol is an essential component of cells and must be present in sufficient quantity for cell proliferation, ie cell division. Inhibition of cell proliferation by inhibition of cholesterol biosynthesis has been described for smooth muscle cells using the HMG-CoA-reductase inhibitor of mevinolin lovastatin, as described above.
An example of a disease associated with excessive cell proliferation is a primary tumor disease. In cell culture and in-vivo experiments, reduction of serum cholesterol or intervention of cholesterol biosynthesis by HMG-CoA-reductase inhibitors has been shown to reduce tumor growth (Lancet 339, 1154-1156 [199].
2)). Therefore, the compounds of formula I of the present invention are potentially suitable for treating tumor diseases on the basis of their inhibitory effect on cholesterol biosynthesis. They may be used alone or in support of known therapeutic principles.

Other examples are hyperproliferative skin disorders such as psoriasis, basal cell carcinoma, squamous cell carcinoma, keratosis and keratinizing disorders. The term "psoriasis" as used herein
Represents a hyperproliferative inflammatory skin disease that alters the skin's regulatory mechanisms. In particular, trauma is formed, which includes primary and secondary alterations of epidermal proliferation, inflammatory responses of the skin and expression of regulatory molecules such as lymphokines and inflammatory factors. Psoriatic skin morphs with increased turnover of epidermal cells, hypertrophic epidermis, abnormal keratinization of inflammatory cell infiltrates into the dermis layer, and polymorphonuclear leukocyte infiltration into the epidermis, resulting in increased basal cell cycle It is a characteristic of the university. In addition, there are keratinocytes and parakeratotic cells. "Keratosis",
The terms "basal cell carcinoma", "squamous cell carcinoma" and "keratinizing disorder" relate to hyperproliferative skin disorders in which the regulatory mechanisms of skin cell proliferation and differentiation are perturbed. The compounds of formula I are effective as antagonists of skin hyperproliferation, ie agents which suppress the hyperproliferation of human keratinocytes. As a result, these compounds
It is suitable as a medicament for treating hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, keratinizing diseases and keratosis. To treat these disorders, the compounds of formula I may be administered orally or topically and may be used alone in the form of monotherapy or in combination with known active substances.

Stenosis and blood vessels based on hyperproliferative vascular disease, eg smooth muscle cell proliferation, and caused by surgery, eg PTCA (percutaneous transluminal coronary angioplasty) or bypass surgery. Occlusion should also be mentioned. As mentioned above, this cell proliferation is known to be suppressed by mevinolin type HMG-CoA-reductase inhibitors such as lovastatin. In view of their inhibitory activity on cholesterol biosynthesis,
The compounds of general formula I are also suitable for the treatment and prophylaxis of these diseases and may be used alone or in combination with known active substances, for example intravenously administered heparin, preferably by oral administration. . Another possible use of the compounds of general formula I according to the invention is the prevention and treatment of gallstone problems. The formation of gallstones is induced by cholesterol concentrations in bile that exceed the maximum solubility of cholesterol in bile, precipitating cholesterol in the form of gallstones. Lipid-lowering substances from the fibrate class lead to increased precipitation of neutral steroids by bile and also an increased tendency to form gallstones. In contrast, cholesterol biosynthesis inhibitors such as lovastatin or pravastatin do not lead to increased gallstone formation. On the contrary, they can lead to a decrease in the cholesterol concentration in the bile, and thus the so-called gallstone formation index, which is a measure of the potential for gallstone formation. This is Gut 31, 348-350 [1990] and Z. Gastroe.
nterol. 29, 242-245 [1991]. Furthermore, the efficacy of lovastatin in the dissolution of gallstones, especially in combination with ursodeoxy bile acid, is
02, No. 4, Pt. 2, A 319 [1992].
Therefore, in view of their mode of action, the compounds of general formula I are also important for the prevention and treatment of gallstone problems. They may be used alone or in combination with known treatments, for example treatment with ursodeoxybile acids, or shock wave lithotripsy and are preferably administered orally.

Finally, the compounds of the general formula I are used for the treatment of infectious diseases caused by pathogenic fungi, such as Candida albicans, Aspergillus niger, Trichophyton mentaglophytes, Penicillium sp., Cladosporium sp. Are suitable. As mentioned above, the final product of sterol biosynthesis in fungal organisms is not cholesterol, but ergosterol, which is essential for the integrity and function of the fungal cell membrane. Therefore, suppression of ergosterol biosynthesis results in impaired growth and possibly death of fungal organisms. For the treatment of mycosis, the compounds of general formula I may be administered orally or topically. They are alone or intervene in known antifungal actives, especially other stages of sterol biosynthesis, such as the squalene-epoxidase inhibitors terbinafine and naphthifine or the azole form of lanosterol-14α-demethylase inhibitors, For example, it may be used in combination with ketoconazole and fluconazole.

Another possible use of the compounds of the general formula I is their application in poultry raising. It has been described that administration of HMG-CoA-reductase inhibitors to laying chickens reduces the cholesterol content of eggs (F
ASEB Journal 4, A 533, Abstracts 1543 [1990]).
The production of low cholesterol eggs is important. What if
This is because the body's cholesterol loading can be reduced by eggs having a reduced cholesterol content without changing eating habits. In view of their inhibitory activity on cholesterol biosynthesis, the compounds of general formula I can also be used in poultry raising for the production of low cholesterol eggs, these substances being preferably administered to chickens as a feed additive. The biological activity of the compound of general formula I was measured by the following method. .. I. Measurement of ¹⁴ C-acetate tori inclusive suppression of steroid that can be precipitated with digitonin: J. Lipid Res 37, using the method described in 148-157 [1996], the inhibitory effect 10 ^- The test concentrations were ⁸ mol / l and 10 ^-9 mol / l. For example, a compound of general formula I
The test results at these test concentrations for (A)-(M) and comparative substances (U), (V) and (W) are shown:

(A) N- (benzylthio) thiocarbonyl-4-
[4- (Dimethylaminomethyl) phenylthio] piperidine hydrochloride, (B) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine hydrochloride, (C) N-benzyloxycarbonyl- 4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, (D) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, (E) N- (Benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride, (F) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine hydrochloride, ( G) N- (4-chlorophenoxy) thiocarbonyl-4- [4- (dimethylaminomethyl) -benzyl] piperidine hydrochloride, (H) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethyl Aminomethyl) benzyl] piperi Hydrochloride, (I) N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride, (K) 4- [4- (dimethylaminomethyl) benzyl] -N- (4- Methylphenoxy) -carbonylpiperidine hydrochloride, (L) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) -thiocarbonylpiperidine hydrochloride, (M) 4- [4- (dimethyl Aminomethyl) benzyl] -N- (4-fluorophenoxy) -carbonylpiperidine hydrochloride, (U) 1- (4-chlorobenzoyl) -4- [4- (2-oxazoline-2-
Yl) -benzylidene) -piperidine (EP-A-0 596 326, p.
16, Compound A therein; J. Lipid. Res. 38, 564-575
(1997)), (V) trans-N- (4-chlorobenzoyl) -N-methyl- [4- (4
-Dimethylamino) -methyl] phenyl] cyclohexylamine (DE-A-44 38 020; J. Lipid. Res. 37, 148-157.
(1996)) and (W) trans-O- (p-tolylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol (WO 95/29148,
p. 28, compound I therein. The percent inhibition of ¹⁴ C-acetate uptake by the above compounds is shown in Table 1.

[0035]

[Table 1]

The IC ₅₀ values of compounds H, I, K and M were determined. These are shown in Table 2 together with the IC ₅₀ values for compounds U, V and W.

[0037]

[Table 2]

Table 2 shows that the compounds of the invention are significantly superior to the comparative substances. II. Determination of in-vivo activity in rats after oral administration Inhibition of the enzyme 2,3-epoxysqualene-lanosterol-cyclase results in an increase in liver and plasma levels of 2,3-epoxysqualene. Therefore, the amount of 2,3-epoxysqualene produced can be used as a direct measure of efficacy on animals as a whole. J. Lipid. Res. 38, 564-575
Using the method described in (1997), the amount is c = 0.
It was measured at t = 3 or 8 hours after the administration of substances having concentrations of 01, 0.03, 0.1, 0.3 and 1.0 mg / kg. Table 3 below shows the results obtained for the above substances A, B, C, D, E, G, H, I and K by way of example.

[0039]

[Table 3] 2,3-epoxysqualene concentration in liver (rat) [μg / g]

In control animals, 2,3-epoxysqualene levels could not be measured under these conditions. III. Lipid reduction in normolipaemic golden hamsters This was measured using the method described in J. Lipid. Res. 38, 564-575, (1997). At the end of the experiment, total cholesterol, β-lipoprotein-cholesterol and
HDL-cholesterol was measured and compared to that of a control group fed without the test substance. The above lipid lowering activity of compound H was tested. The results are shown in Table 4.

[0041]

[Table 4]

Under these conditions, the compound showed no toxic effects. IV. Measurement of fungistatic activity The fungistatic activity was measured by a series of dilution tests (microtiter system). Sublobulose was used as the nutrient medium. The inoculum was in an amount of about 10 ⁴ to 10 ⁵ CFU / ml (CFU = colony forming unit). Incubation period is 26 ℃ 2
It was ~ 4 days. The lowest concentration (minimum inhibitory concentration MIC) that does not allow visible growth was measured. The compounds A, B,
D, E, F, H, I, K, L and M were tested. The results are summarized in Table 5 below. MICs are given in μg / ml. The following test pathogens were used. Test agent Abbreviation Candida albicans ATCC 10231 Cand. Sacch. Calsbergensis ATCC 9080 Sacc. Rhodotorula rubra 49 Rhod. Aspergillus niger ATCC 16404 Asp. Trichophyton mentaglophytes ATCC 9129 Trich. Penicillium notatum CBS 19746 Pen.

[0043]

[Table 5]

For pharmaceutical use, the compounds of general formula I are
It can be incorporated into the usual pharmaceutical preparations for oral, rectal and topical administration in a manner known per se. Formulations for oral administration include, for example, simple and coated tablets and capsules. For rectal administration, suppositories may be used. The daily dosage is 0.1 m for a 60 kg person.
Although g to 200 mg, the preferred daily dosage is 1 mg to 100 mg for a 60 kg person. Daily dosage is 1-3
It is preferably divided into individual doses. For topical application, the compound is about 1-1000 mg daily, especially 10-300 m
It can be administered in a formulation containing g of active substance. The daily dosage is preferably divided into 1 to 3 individual dosages. Topical formulations include gels, creams, lotions, ointments, powders, aerosols and other conventional formulations for applying drugs to the skin. The amount of active substance for topical use is from 1 to 50 mg per gram of formulation, preferably from 5 to 20 mg per gram of formulation. Apart from application to the skin, the topical formulations of the present invention may also be used for the treatment of mucous membranes susceptible to topical treatment. For example, the topical formulation may be applied to the mucous membranes of the mouth, lower colon and the like. For use in poultry raising for the production of low-cholesterol eggs, the active substances of general formula I are administered to animals by conventional methods as suitable food additives. The concentration of the active substance in the finished feed is usually 0.01 to 1
%, Preferably 0.05 to 0.5%. The active substance may be added to the feed as it is. Thus, the chicken egg-laying feed according to the invention comprises, for example, corn, soybean meal, meat meal, feed fat and soybean oil in addition to the active substance and optionally the usual vitamin-mineral mixtures. To this feed, one of the compounds of formula I as active substance
It is added at a concentration of 1%, preferably 0.05-0.5%. The following examples can be used to more fully illustrate the present invention. The R _f values shown were determined on ready-made plates obtained from E. Merck, Darmstadt, a) aluminum oxide F-254 (type E) b) silica gel 60 F-254.

EXAMPLES Example of Preparation of Starting Materials: Example A 4- [4- (Dimethylaminomethyl) phenylthio] piperidi
To a solution of 7.18 g (71 mmol) of 4-hydroxypiperidine in 100 ml of dimethylformamide was first added 19.6 g (142 mmol) of powdered potassium carbonate, then 19.8 g of trityl chloride.
(71 mmol) is added. The mixture at ambient temperature 22
Stir for 2 hours, dilute to twice volume with ethyl acetate, wash with water and saturated sodium chloride solution, dry over magnesium sulfate,
Concentrate by evaporation. The residue is recrystallized with ethyl acetate / petroleum ether (1: 4, v: v). 17.65 g (72.4% of theory) of 4-hydroxy-N-tritylpiperidine are obtained as colorless crystals, melting point 157-158 ° C. 5.77 g of this product are dissolved in 60 ml of methylene chloride, 2.6 g of methanesulphonic acid chloride are added and 3.4 g of triethylamine are slowly added dropwise.
The mixture was stirred at 0 ° C. for 1 hour, diluted with ether,
Wash with ice water (4x), dry over magnesium sulfate and concentrate by evaporation. 7.58 g of 4-methanesulfonyloxy-N-tritylpiperidine are obtained as a colorless foam.

The product is dissolved in 30 ml of tetrahydrofuran and a solution of the sodium salt of 4-bromothiophenol (4-bromothiophenol 3.18 in 35 ml of tetrahydrofuran is added).
g and 55% sodium hydride 0.81 g). It is heated to boiling for 1 hour, cooled, then taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. 4.28 g of 4- (4-bromophenylthio) -N-tritylpiperidine are obtained as colorless crystals, melting point 174-175 ° C. 2.57 g (5 mmol) of this product are dissolved in 30 ml of tetrahydrofuran and at −70 ° C. 4 ml (6.4 mmol) of a 1.6 molar solution of n-butyllithium in n-hexane are added dropwise. After 1.5 hours at -70 ° C, 1.1 g (6.4 mmol) N, N-dimethyl-methyleneimmonium-iodide are added, the cooling bath is removed and the mixture is stirred overnight. The solvent is evaporated, the residue is triturated with water and extracted with ethyl acetate.
The organic phase is dried over magnesium sulphate, concentrated by evaporation and the residue is purified by column chromatography (aluminum oxide, ethyl acetate / petroleum ether = 1: 10, v: v). 4- [4- (dimethylaminomethyl) phenylthio]
-N-Trityl-piperidine 0.9g colorless crystals, melting point 163 ° C
Get as. Dissolve this product in 30 ml of methylene chloride,
10 ml of ethereal hydrochloric acid are added. After 1 hour at ambient temperature, the mixture is concentrated by evaporation, combined with ether and the precipitate is suction filtered. This is dissolved in a little water, ether is added and the mixture is adjusted to pH 11 with 6N sodium hydroxide solution. The ether phase is separated off, the aqueous phase is extracted again with ether and the combined extracts are dried over magnesium sulphate. 4- [4- (dimethylaminomethyl)
Phenylthio] piperidine 500 mg as colorless crystals, melting point 52
Obtained as ° C.

Example B 4- [4- (Piperidinomethyl) phenylthio] piperidine 10.1 g (0.1 mol) of 4-hydroxypiperidine and 11 g (0.11 mol) of triethylamine were placed in 200 ml of ethyl acetate and 250 ml of tetrahydrofuran, and 2,2,2-trichloro A solution of 23.3 g (0.11 mol) of ethyl chloroformate is added dropwise at 0-4 ° C. The mixture is stirred at 0 ° C. for 1 hour and at ambient temperature for 1 hour. The precipitate is suction filtered and the filtrate is -12
Combined with 12 g (0.105 mol) of methanesulfonic acid chloride at ℃ to -14 ℃, 50 ml of tetrahydrofuran at -8 ℃ to -12 ℃
12 g (0.12 mol) of triethylamine in are added dropwise. Stir it at -10 ° C for 40 minutes, remove the cooling bath,
The mixture is stirred for 30 minutes. After washing with water and saturated saline solution, it is dried over magnesium sulphate, concentrated by evaporation, the residue is triturated with diisopropyl ether and suction filtered. 4-Methanesulfonyloxy-N-2,2,2-trichloroethoxycarbonylpiperidine 32.4 g (theoretical value of 9
1.5%) as colorless crystals, melting point 93 ° C. 17.7 g (50 mmol) of this product in 30 ml of dimethylformamide
Is added dropwise at ambient temperature to a solution of potassium thiophenoxide (prepared from 6 g thiophenol and 6.2 g potassium-tert.butoxide in 50 ml dimethylformamide at 20-60 ° C.). Combine the resulting jelly-like substance with 100 ml of dimethylformamide, heat to 60 ° C and add 30 ml of methanol.
After addition of, leave overnight at ambient temperature. After addition of 800 ml of water, the mixture is extracted with ether, the ether extracts are washed with water, dried over magnesium sulphate and concentrated by evaporation. After purification by column chromatography (silica gel, petroleum ether / ethyl acetate = 5: 1, v: v), 11 g of 4-phenylthio-N-2,2,2-trichloroethoxycarbonylpiperidine (64.3% of theory) is colorless. Get as oil.

9 g (25 mmol) of this product, 6 g of paraformaldehyde and 5.6 g of zinc chloride (42 mmol) are placed in 300 ml of methylene chloride. Hydrogen chloride is introduced at 20-22 ° C. for 30 minutes. After 1 hour, hydrogen chloride is re-piped for 10 minutes and then the mixture is stirred overnight. The reaction mixture is stirred in 300 ml of 1 molar disodium hydrogen phosphate solution, the methylene chloride phase is separated off and the aqueous phase is extracted with methylene chloride. Combine the organic phases,
Wash with water, dry over magnesium sulfate and concentrate by evaporation. After purification by column chromatography (silica gel, ethyl acetate / petroleum ether = 1: 10, v: v), 4-
[4- (chloromethyl) phenylthio] -N-2,2,2-trichloroethoxycarbonylpiperidine 4.5 g (theoretical value of 43.2
%) As a colorless oil. 2.1 g (5 mmol) of this product and 1.3 g (15 mmol) of piperidine are refluxed in 10 ml of tetrahydrofuran and 10 ml of ethanol for 2.5 hours. After evaporation, the residue is triturated with water and extracted with ether. The ethereal phase is washed with water, dried over magnesium sulphate and concentrated by evaporation. 2.5 g of 4- [4- (piperidinomethyl) phenylthio] -2,2,2-trichloroethoxycarbonylpiperidine are obtained as a crude product. This product
2.4 g is dissolved in 3.5 ml acetic acid and 18 ml water and 5 g zinc powder is added (vigorous foaming). The mixture is stirred for 20 hours at ambient temperature and 1 hour at 50 ° C. After adding 20 ml of water,
A layer of 100 ml of ether is added, the mixture is made strongly alkaline with 6N sodium hydroxide solution and stirred for 20 minutes.
The ether is separated off and the aqueous phase is extracted 3 times with ether. The combined extracts are dried over magnesium sulphate and concentrated by evaporation. 1.3 g of 4- [4- (piperidinomethyl) phenylthio] piperidine are obtained as colorless powder. R _f value:
0.69 (magnesium oxide, methylene chloride / methanol =
10: 1, v: v)

Example C 4- [4- (Dimethylaminomethyl) benzyl] piperidine 100 g (0.57 ) of 4-benzylpiperidine in 220 ml of methanol.
Mole) at 20-35 ℃ 88g of methyl trifluoroacetate
(0.68 mol). After 2 hours, the mixture is concentrated by evaporation. After crystallizing the residue with petroleum ether, 4-benzyl-N-trifluoroacetylpiperidine 117
g (76% of theory) are obtained as colorless crystals. 113 g (0.848 mol) aluminum chloride in 600 ml dichloroethane are combined with 114 g (0.9 mol) oxalyl chloride. -4 to + 4 ° C
Then, 114 g of the above product is added dropwise to 300 ml of dichloroethane (generation of gas). 2.5 the mixture at ambient temperature
Stir for hours, then at -25 ° C, quickly add 300 ml of 40% aqueous dimethylamine solution (temperature rises to 35 ° C). The jelly formed is diluted with 100 ml dichloroethane, stirred for 20 minutes and diluted with chloroform to improve phase separation. Water it, 2N sodium hydroxide solution,
Wash with water, 2N hydrochloric acid and again with water. The organic phase is dried over magnesium sulphate, concentrated by evaporation and the residue triturated with ether. 111 g (80% of theory) of 4- [4- (dimethylaminocarbonyl) benzyl] -N-trifluoroacetylpiperidine are obtained as colorless crystals. 64 g of this product in 350 ml of tetrahydrofuran is added dropwise to 70 ml of a 20% solution of lithium aluminum hydride in ether at 0-3 ° C and diluted with 250 ml of ether. It is stirred at 0 ° C. for 20 minutes and then refluxed for 1 hour. At 0-15 ° C., 40 ml of 4N sodium hydroxide solution are added dropwise (vigorous foaming), stirred for 30 minutes at ambient temperature, suction filtered and the filter residue is washed with ether. The combined ethereal phases are dried over magnesium sulphate and concentrated by evaporation. Four-
[4- (Dimethylaminomethyl) benzyl] piperidine 46g
(99% of theory) are obtained as a colorless gradually crystallizing oil. R _f value: 0.56 (aluminum oxide, methylene chloride / methanol = 10: 1, v: v)

Example of Preparation of Final Product Example 1 N- (benzylthio) thiocarbonyl-4- [4- (dimethylamido)
Nomethyl) phenylthio] piperidine hydrochloride 4- [4- (dimethylaminomethyl ) phenylthio] piperidine 237 mg (0.83 mmol), triethylamine 200 mg (2
Mmol) and 1 ml of ethanol are combined at ambient temperature with 150 mg (2 mmol) of carbon disulfide. The precipitate formed was mixed with 1 ml of triethylamine and 2.5 of dimethylformamide.
Dissolve by adding ml. After 1 hour at ambient temperature, 160 mg (0.94 mmol) benzyl bromide are added, it is stirred overnight at ambient temperature and then heated to 60 ° C. for 3 hours. After addition of 50 ml of water, the mixture is extracted with ethyl acetate, the organic phase is dried over magnesium sulphate and concentrated by evaporation. After purification of the residue by column chromatography (aluminum oxide, petroleum ether / ethyl acetate = 4: 1, v: v), 210 mg of the title compound are obtained as a colorless oil, which is converted to the hydrochloride salt with ethereal hydrochloric acid. R _f value of free base: 0.83 (aluminum oxide, ethyl acetate / petroleum ether = 3: 1, v: v) ¹ H-NMR spectrum (200 MHz, DMSO-d ₆ ), signal (pp
m): 1.4-1.6 (m, 2H), 2.0-2.15 (m, 2H), 2.55 (d, 6H),
3.5-3.65 (t, 2H), 3.7-3.85 (m, 1H), 4.2 (d, 2H),
4.3-4.4 (m, 1H), 4.5 (s, 2H), 4.95-5.15 (m, 1H),
7.2-7.6 (m, 9H)

Similarly, the following compounds are obtained. (1) From N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) benzoyl] piperidine and benzyl bromide; colorless powder; R _f value of free base:
0.65 (aluminum oxide, ethyl acetate) (2) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) benzylidene] piperidine and odor From benzyl chloride; colorless powder; melting point: 190 ° C. (3) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) benzyl ] From piperidine and benzyl bromide; colorless powder; R _f value of free base: 0.
26 (aluminum oxide, petroleum ether / ethyl acetate = 1
0: 1, v: v)

Example 2 N-benzyloxycarbonyl-4- [4- (dimethylaminometh
Tyl) phenylthio] piperidine 250 mg (1 mmol) of 4- [4- (dimethylaminomethyl ) phenylthio] piperidine in 20 ml of tetrahydrofuran
Combine with 2 ml of 2N sodium hydroxide solution and 5 ml of water. At ambient temperature, 200 mg (1.2 mmol) of benzyl chloroformate in 5 ml of tetrahydrofuran are slowly added dropwise. After 1.5 hours at ambient temperature, some benzyl chloroformate and sodium hydroxide solution are added again.
After addition of 100 ml of ether, the mixture is washed with saturated saline solution, the organic phase is dried over magnesium sulphate and concentrated by evaporation. The product obtained after purification by column chromatography (aluminum oxide, petroleum ether / ethyl acetate = 4: 1, v: v) is converted to the hydrochloride with ethereal hydrochloric acid. 190 mg (45.1% of theory) of the title compound are obtained as a colorless powder, melting point 144 ° C. ¹ H-NMR spectrum (200 MHz, DMSO-d ₆ ), signal (pp
m): 1.3-1.5 (m, 2H), 1.85-2.0 (m, 2H), 2.65 (s, 6H),
2.95-3.15 (t, 2H), 3.5-3.65 (m, 1H), 3.8-4.0 (m, 2
H), 4.2 (s, 2H), 5.05 (s, 2H), 7.3-7.6 (m, 9H)

Similarly, the following compounds are obtained. (1) N- (4-chlorophenylthio) thiocarbonyl-4- [4-
From (dimethylaminomethyl) phenylthio] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) phenylthio] piperidine and 4-chlorophenylchlorodithioformate;
Colorless powder; melting point: 178 ° C (2) 4- [4- (dimethylaminomethyl) phenylthio] -N-phenoxycarbonylpiperidine hydrochloride, 4- [4- (dimethylaminomethyl) phenylthio] piperidine and phenylchloroformate From; colorless powder; melting point: 161 ° C (3) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) phenylthio ] From piperidine and 4-chlorophenyl chloroformate; colorless powder; melting point: 169 ° C (4) 4- [4- (dimethylaminomethyl) phenylthio] -N-
From (phenylthio) thiocarbonylpiperidine hydrochloride, 4- [4- (dimethylaminomethyl) phenylthio] piperidine and phenylchlorodithioformate; colorless powder; R _f value of free base: 0.57 (aluminum oxide, petroleum ether / acetic acid Ethyl = 4: 1, v: v) (5) N-4- (4-chlorophenoxy) thiocarbonyl-4- [4-
From (dimethylaminomethyl) benzyl] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) benzyl] piperidine and O-4-chlorophenylchlorothioformate; colorless powder; melting point: 150 ° C.

(6) N- (4-chlorophenoxy) carbonyl-4-
From [4- (dimethylaminomethyl) benzyl] piperidine, 4- [4- (dimethylaminomethyl) benzyl] piperidine and 4-chlorophenylchloroformate; melting point of free base: 104 ° C. Treatment of its hydrochloride with hydrochloric acid. Obtained by. Colorless powder; melting point: 156 ° C. The methanesulfonate was obtained by treating the free base with methanesulfonic acid in an ethyl acetate-ether mixture. Colorless powder; melting point: 152 ° C. The tartrate salt was obtained by treating the free base with L-tartaric acid in a methanol-ethyl acetate mixture. Colorless powder; melting point: 147 ° C (7) N- (4-chlorophenylthio) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride, 4- [4- (dimethylaminomethyl) benzyl] piperidine And S-4-chlorophenylchlorothioformate; colorless powder; melting point: 190-191 ° C (8) N-benzyloxycarbonyl-4- [4- (piperidinomethyl) phenylthio] piperidine hydrochloride, 4- [4- From (piperidinomethyl) phenylthio] piperidine and benzyl chloroformate; colorless powder; melting point:
186 ℃ (9) N-phenoxycarbonyl-4- [4- (piperidinomethyl)
From phenylthio] piperidine hydrochloride, 4- [4- (piperidinomethyl) phenylthio] piperidine and phenylchloroformate; colorless powder; melting point:
204 ° C (10) From N-4-chlorophenoxycarbonyl-4- [4- (piperidinomethyl) phenylthio] piperidine hydrochloride, 4- [4- (piperidinomethyl) phenylthio] piperidine and 4-chlorophenylchloroformate; colorless powder Melting point: 182 ° C

(11) N-benzyloxycarbonyl-4- [4-
From (dimethylaminomethyl) benzyl] piperidine, 4- [4- (dimethylaminomethyl) benzyl] piperidine and benzyl chloroformate; melting point of free base: 63
C was obtained by treating the hydrochloride salt with hydrochloric acid. Colorless powder; melting point: 132 ° C. The methanesulfonate was obtained by treating the free base with methanesulfonic acid in an ethyl acetate-ether mixture. Colorless powder; melting point: 140 ° C. The tartrate salt was obtained by treating the free base with L-tartaric acid in a methanol-ethyl acetate mixture. Colorless powder; melting point: 125 ° C. (12) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) carbonylpiperidine, 4- [4- (dimethylaminomethyl) benzyl] piperidine and 4 From methylphenyl chloroformate; melting point of free base: 80 ° C. Obtained by treating the hydrochloride salt with hydrochloric acid. Colorless powder; melting point: 185 ° C. The methanesulfonate was obtained by treating the free base with methanesulfonic acid in an ethyl acetate-ether mixture. Colorless powder; melting point: 165 ° C. The tartrate salt was obtained by treating the free base with L-tartaric acid in a methanol-ethyl acetate mixture. Colorless powder; melting point: 162 ° C (13) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) thiocarbonylpiperidine hydrochloride, 4- [4- (dimethylaminomethyl) benzyl] From piperidine and O-4-methylphenylchlorothioformate; colorless powder; melting point: 184 ° C (14) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-fluorophenoxy) carbonylpiperidine hydrochloride , 4- [4- (dimethylaminomethyl) benzyl] piperidine and 4-fluorophenyl chloroformate; colorless powder; R _f value of free base: 0.61 (aluminum oxide; petroleum ether / ethyl acetate = 6: 1, v: v)

Example 3 N-benzyloxycarbonyl-4- [4- (dimethylaminometh
Tyl) phenylsulfinyl] piperidine hydrochloride N-benzyloxy-4- [4- (dimethylaminomethyl) -phenylthio] piperidine hydrochloride 90.7 mg (0.215 mmol)
Is dissolved in a mixture of 1 ml of methanol and 1 ml of water and first 18.6 mg (0.226 mmol) of anhydrous sodium acetate and then 48.4 mg (0.226 mmol) of sodium metaperiodate are added. The mixture was stirred at ambient temperature for 6 hours, diluted with water, covered with ethyl acetate and saturated with sodium carbonate. The organic phase is separated off, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated saline solution, dried over magnesium sulphate and concentrated by evaporation. The residue is dissolved in a little methylene chloride, combined with ethereal hydrochloric acid and the solvent evaporated. Triturate the residue with ether, evaporate the solvent,
The residue is dried under high vacuum. 85 mg of the title compound (theoretical
90.5%) as a colorless powder. R _f value of free base: 0.43 (aluminum oxide, ethyl acetate / petroleum ether = 1: 1, v: v) ¹ H-NMR spectrum (200 MHz, DMSO-d ₆ ), signal (pp
m): 1.3-1.6 (m, 3H), 1.8-2.0 (m, 1H), 2.65 (s, 6
H), 2.7-3.1 (m, 3H), 3.95-4.15 (t, 2H), 4.35 (s, 2
H), 5.05 (s, 2H), 7.3 (s, 5H), 7.65-7.85 (q, 4H)

Similarly, the following compounds are obtained. (1) 4- [4- (dimethylaminomethyl) phenylsulfinyl] -N-phenoxycarbonylpiperidine hydrochloride, 4- [4- (dimethylaminomethyl) phenylthio] -N-phenoxycarbonylpiperidine hydrochloride and metaperiodic acid From sodium; colorless powder; R _f value of free base: 0.4
(Aluminum oxide, ethyl acetate / petroleum ether = 1:
1, v: v)

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI A61P 9/10 A61P 9/10 31/10 31/10 43/00 111 43/00 111 C07D 211/26 C07D 211/26 211 / 32 211/32 211/70 211/70 // A23K 1/16 302 302 A23K 1/16 302J (72) Inventor Mueller Peter United States Connecticut 06903 Stamford Millstream Road 71 (72) Inventor Sylcher Gephardt German Federation Republic Day 88441 Mitterl Biberach Ahornweg 1 (72) Inventor Adel Goss Gephard Germany Day 88400 Biberach Geschwister Schorstraße 75 (72) Inventor Frunaus Rudolf German Day 88400 Biberach Rucherstraße 19 (72) Inventor Mark Michel Germany Day 88400 Biberach Hugo Heringstraße 50 (72) Inventor Eisele Bernhardt Germany Day 88400 Biberach Beethovenstraße 12 (56) Reference West Germany Patent application publication 4407138 (DE, A1) West German patent application publication 4407136 (DE, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 211/06-211/78 REGISTRY (STN) CA ( STN) CAOLD (STN)

Claims (16)

(57) [Claims] 1. A compound of general formula (I), enantiomers thereof, diastereomers, mixtures and salts thereof. [Chemical 1] (In the formula, m represents a number 0 or 1, n represents a number 1 or 2, A is a single bond, a linear or branched C _1-8 -alkylene group, C _2-8 -alkenylene group or C _2-. Represents an ₈ -alkynylene group (unsaturated group is not directly bonded to the group Y), X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, R ¹ is a linear or branched C _{1 -6} -alkyl group, C _1-4 -alkenyl group or C _1-4 -alkynyl group, the multiple bond of which is nitrogen-
Separated from carbon bond, R ² represents a linear or branched C _1-6 -alkyl group, C _1-4 -alkenyl group or C _1-4 -alkynyl group, multiple bonds separated from nitrogen-carbon bond Or R ¹ and R ² together with a nitrogen atom represent a 5- to 7-membered saturated heterocycle, and the methylene group separated from the nitrogen atom is an oxygen atom or a sulfur atom or a —NH— group or -N (alkyl)-group may be substituted, R ^{3 to} R ⁶ (which may be the same or different) represent a hydrogen atom or an alkyl group, and R ⁷ represents C _{Represents a 3-7} -cycloalkyl group, a phenyl group or a naphthyl group optionally substituted by one or two halogen atoms or an alkyl group, an alkoxy group, a trifluoromethyl group or a cyano group, or A is if not represent a single bond, R ⁷ is also hydrogen Represents the child, E represents an oxygen atom or a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ represents a hydrogen atom, or E is a group ^{-C (R 9 R 10) -} ( wherein, R ⁹ represents a hydrogen atom, and R ¹⁰ represents a carbon-carbon bond together with the adjacent group R ⁸ ), and unless otherwise specified, the alkyl group contained in the above group is 1 to 3 It may contain a carbon atom, and the halogen atom may be a fluorine atom, a chlorine atom or a bromine atom.) 2. In the formula, m represents the number 1, n represents the number 1, A represents a single bond, a linear or branched C _1-4 -alkylene group or C _2-4-.
Represents an alkenylene group, the unsaturated group is not directly bonded to the group Y, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, R ¹ is a straight chain or branched C _1-6 -An alkyl group, an allyl group or a propargyl group, the multiple bond of which is separated from the nitrogen-carbon bond, R ² represents a linear or branched C _1-6 -alkyl group, an allyl group or a propargyl group, The multiple bond is separated from the nitrogen-carbon bond, R ¹ and R ² together with the nitrogen atom represent a 5-membered to 7-membered saturated heterocycle, and the methylene group separated from the nitrogen atom is an oxygen atom or It may be substituted by a sulfur atom, R ^{3 to} R ⁶ (which may be the same or different) represent a hydrogen atom or a methyl group, and R ⁷ represents C _3-6 -cyclo Alkyl group, optionally 1 or 2 halogen atoms or Alkyl group, an alkoxy group, a trifluoromethyl group or an optionally substituted phenyl or naphthyl group by a cyano group, E represents a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ is a hydrogen atom Or E represents the group -C (R ⁹ R ¹⁰ )-(wherein R ⁹ represents a hydrogen atom, and R ¹⁰ together with the adjacent group R ⁸ represents a carbon-carbon bond). Unless otherwise specified, the alkyl groups contained in the above groups may each contain 1 to 3 carbon atoms, and the halogen atoms may be fluorine atoms, chlorine atoms or bromine atoms, A compound of general formula I according to the first paragraph,
Enantiomers, diastereomers, mixtures thereof and salts thereof. 3. m represents the number 1, n represents the number 1, A represents a single bond or a linear or branched C _1-3 -alkylene group, X represents an oxygen atom or a sulfur atom, and Y represents Represents an oxygen atom or a sulfur atom, R ¹ represents a linear or branched C _1-3 -alkyl group, R ² represents a linear or branched C _1-3 -alkyl group, or R ¹ and R ² are nitrogen Together with the atom represents a piperidino group or a morpholino group, R ^{3 to} R ⁶ represent a hydrogen atom, R ⁷ is a cyclohexyl group or optionally substituted by a halogen atom or an alkyl group, an alkoxy group or a trifluoromethyl group. Optionally represents a phenyl group, E represents a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ represents a hydrogen atom, or E represents a group -C (R ⁹ R ¹⁰ )-(in the formula, R ⁹ represents a hydrogen atom, and R ¹⁰ is a carbon, together with the adjacent group R ⁸ - carbon bond Represents a represents), compounds of general formula I according claim 1, wherein, their enantiomers, diastereomers, mixtures and salts thereof. 4. m represents the number 1, n represents the number 1, A represents a single bond or a methylene group, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, R ¹ and R ² each represent a methyl group, R ^{3 to} R ⁶ each represent a hydrogen atom, R ⁷ represents a phenyl group optionally substituted by a fluorine atom or a chlorine atom or a methyl group, and E represents sulfur. An atom, a methylene group or a carbonyl group, and R ⁸ represents a hydrogen atom, or E represents a group -C (R ⁹ R ¹⁰ )-(in the formula, R ⁹ represents a hydrogen atom, and R ¹⁰ represents an adjacent group. R ⁸ together with C ⁸ represents a carbon-carbon bond) A compound of the general formula I as defined in claim 1, mixtures thereof and salts thereof. (5) (1) N- (benzylthio) thiocarbonyl-4-
[4- (dimethylaminomethyl) phenylthio] piperidine, (2) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine, (3) N-benzyloxycarbonyl-4- [4 -(Dimethylaminomethyl) phenylthio] piperidine, (4) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (5) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (6) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine, (7) N- (4-chlorophenoxy) thiocarbonyl -4- [4- (dimethylaminomethyl) -benzyl] piperidine, (8) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (9) N-benzyloxy Carbonyl-4- [4- (di (Cylaminomethyl) benzyl] piperidine, (10) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) -carbonylpiperidine, (11) 4- [4- (dimethylaminomethyl) benzyl ] -N- (4-Methylphenoxy) -thiocarbonylpiperidine and (12) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-fluorophenoxy) -carbonylpiperidine, Compounds of general formula I as defined under paragraph, mixtures thereof and salts thereof. 6. A physiologically acceptable salt of the compound according to at least one of claims 1 to 5 with an inorganic or organic acid. 7. One or more inert carriers and / or if necessary
Or a pharmaceutical composition comprising a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 together with a diluent. 8. A pharmaceutical composition according to claim 7, which is suitable for treating diseases in which cholesterol biosynthesis plays a role. 9. A compound according to at least one of claims 1 to 5 or a compound according to claim 6 in combination with one or more other active substances having cholesterol-lowering or lipid-lowering activity. The pharmaceutical composition according to claim 8, comprising a physiologically acceptable salt. 10. A resin in which other active substance binds bile acid, a compound that suppresses cholesterol absorption, a compound related to cholesterol biosynthesis by a mechanism other than the suppression of 2,3-epoxysqualene-lanosterol-cyclase, fibrate, 10. The pharmaceutical composition according to claim 9, which is selected from nicotinic acid, derivatives and analogs thereof, and probucol. 11. A claim for treating or preventing hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, coronary heart disease, cerebral ischemia, intermittent gangrene or gangrene, or treating mycosis. Range 8, 9 or 10
Item 6. A pharmaceutical composition according to item. 12. The method according to any one of claims 7 to 11.
Use of a compound according to at least one of claims 1 to 5 as a cholesterol biosynthesis inhibitor for the preparation of a pharmaceutical composition . 13. The compound according to claim 1, wherein the compound according to at least one of claims 1 to 6 is mixed with one or more inert carriers and / or diluents by a non-chemical method. A method for preparing the pharmaceutical composition according to item 7. 14. A) General formula: Wherein m, n, E (excluding sulfinyl group), R ^{1 to} R ⁶ and R ⁸ are as defined in claims 1 to 5. 3] Where A, X, Y and R ⁷ are as defined in claims 1 to 5 and Z represents a leaving group, and optionally, The mixture of geometric isomers of the compound of general formula I thus obtained is resolved into its enantiomers and diastereomers, or the compound of general formula I thus obtained is treated with an inorganic or organic acid and its salts, in particular its 7. The method for preparing a compound according to at least one of claims 1 to 6, which comprises converting into a physiologically acceptable salt. 15. A compound of the general formula (I) according to claim 1, wherein X and Y each represent a sulfur atom, and m, n, A, E and R ^{1 to} R ⁸ are Is as defined in the first to fifth ranges, provided that when A represents a single bond, R ⁷ does not represent an optionally substituted phenyl group or naphthyl group. To prepare a compound of general formula (II) according to claim 14 (wherein
m, n, E (excluding sulfinyl group), R ^{1 to} R ⁶ and R ⁸ are as defined in claims 1 to 5.
Is reacted with carbon disulfide, followed by general formula (IV) (In the formula, A and R ⁷ are as defined in claims 1 to 5, provided that when A represents a single bond, R ⁷ may be optionally substituted. A phenyl group or a naphthyl group is not represented, and Z ¹ represents a leaving group), and a geometric isomer of the compound of general formula I thus obtained, if desired. A compound of the formula I is resolved into its enantiomers and diastereomers, or the compound of general formula I thus obtained is converted into its salts with inorganic or organic acids, in particular its physiologically acceptable salts. A method for preparing the compound according to at least one of claims 1 to 6. 16. To prepare a compound of general formula (I) according to claim 1, wherein E represents a sulfinyl group, a compound of general formula (I): n, A, X,
Y, and R ^{1 to} R ⁸ are as defined in claims 1 to 5, and E represents a sulfur atom), and, if desired, the general formula thus obtained A mixture of geometric isomers of a compound of I can be resolved into its enantiomers and diastereomers, or a compound of general formula I thus obtained can be converted into its salt with an inorganic or organic acid, especially its physiologically acceptable salt. A method for preparing a compound according to at least one of claims 1 to 6, wherein the compound is converted.